Chronic inflammatory diseases, such as coronary artery disease starts with the formation of atherosclerotic plaques in the coronary arteries. Abrupt occlusion of these atherosclerotic arteries due mainly to thrombosis leads to coronary heart diseases: unstable angina, acute myocardial infarction and sudden death. Coronary artery disease is a disease of several risk factors, among which are hyperlipidemia, hypertension, diabetes mellitus and tobacco smoking. The origin or cause of all stages of atherosclerotic cardiovascular diseases has been implicated by inflammation and is considered to be a major part of the pathophysiological basis of atherogenesis. Atherosclerosis is a degenerative inflammatory process that affects artery walls. Due to the lack of appropriate diagnostic markers, the first clinically presentation of more than half of the patients with coronary artery diseases is either myocardial infarction or death. Thrombotic diseases including myocardial infarction and stroke are currently the leading cause of death in the western world.
Rupture of the fibrous cap in so-called “vulnerable atherosclerotic plaques” is a critical trigger of myocardial infarction and stroke. Thereby vulnerable atherosclerotic plaques become thrombogenic by either rupturing open, or expressing pro-thrombotic agents which promote blood coagulation and occlude the coronary blood flow. Atherothrombosis is a term which describes the blood coagulation derived from atherosclerotic plaques to form so-called occluding “coronary thrombi”. One of the key events involved in promoting plaque instability is degradation of the fibrous cap, which exposes the underlying thrombogenic plaque core to the bloodstream, thereby causing thrombosis and subsequent vessel occlusion. Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets and fibrin to form a blood clot to prevent blood loss.
Alternatively, even when a blood vessel is not injured, blood clots may form in the body if the proper conditions present themselves. When a thrombus occupies a significant surface area of the lumen of an artery, blood flow to the tissue supplied may be reduced to cause symptoms due to decreased oxygen (hypoxia) and accumulation of metabolic products like lactic acid. More than 90% obstruction can result in anoxia, the complete deprivation of oxygen, and infarction, a mode of cell death.
Coronary thrombus formation is orchestrated by myriad proteases whose enzymatic activities promote thrombosis via blood clotting. An understanding of the specific proteins which are expressed on each cell population may allow for identification of novel biomarkers and therapeutic targets against myocardial infarction. In addition, as myocardial infarctions often reoccur, a complete protein/cell description of individuals' thrombi may motivate personalized preventative treatment against reoccurring events. Unfortunately, the level of specific cell population as well as the proteins expressed by specific cell populations and their respective expression levels in coronary thrombi remain unknown.
It was not until 1980 that DeWood et al. (N Engl J Med 303 (1980), 897-901) provided definitive angiographic evidence that intracoronary thrombi have a causal role in the pathogenesis of acute coronary occlusion in acute myocardial infarction. Since then, coronary thrombi have proven practically difficult to retrieve from the infracted heart of living patients for diagnostics or pre-clinical research. However, recent advances in thrombus-retrieving catheter technology now allow well-equipped catheter labs to retrieve coronary thrombus material for analysis.
Nevertheless, though research in the process of the onset and development of chronic inflammatory disease have developed, means and methods of therapeutic intervention as well as a reliable diagnosis of conditions related to inflammatory and/or cardiovascular diseases still often suffer from severe side effects, low efficacy and unreliable prediction of disease state to name a few short-comings encountered in the art. This is probably because though a magnitude of possible novel therapeutic and diagnostic targets as well as methods of determining the same have been suggested, a reliable ex-vivo assay for selecting putative drugs and lead compounds for the development of a therapeutic and diagnostic agent for inflammatory and cardiovascular diseases has not been established yet.
Thus, there is a need for novel candidate therapeutic and diagnostic molecules capable of neutralizing and detecting pro-thrombotic targets, and which are specific to targeted cell populations for optimal safety and efficacy. In addition, candidate therapeutic or diagnostic molecules should specifically target cell populations involved in thrombus formation and not quiescent peripheral blood, as undesired side-effects may occur.
The solution to said technical problem is achieved by providing the embodiments as characterized in the claims and described further below.